This invention relates generally to a novel method of using interferon in low dosages to regulate appetite and efficiency of food utilization in warm-blooded vertebrates. This invention also relates to the novel use of interferon in low dosages to prevent and treat bovine respiratory disease complex.
"Interferon" is a term generically comprehending a group of vertebrate glycoproteins and proteins which are known to have various biological activities, such as antiviral, antiproliferative, and immunomodulatory activity in the species of animal from which such substances are derived. The following definition for interferon has been accepted by an international committee assembled to devise a system for the orderly nomenclature of interferons: "To qualify as an interferon a factor must be a protein which exerts virus nonspecific, antiviral activity at least in homologous cells through cellular metabolic processes involving synthesis of both RNA and protein." Journal of Interferon Research, 1, pp. vi (1980).
Since the first descriptions of interferon by Isaacs and Lindeman see, Proc, Roy, Soc. London (Ser. B), Vol. 147, pp. 258 et sea. (1957) and U.S. Pat. No. 3,699,222!, interferon has been the subject of intensive research on a worldwide basis. Publications abound concerning the synthesis of interferon; M. Wilkinson and A. G. Morris, Interferon and the Immune System 1: Induction of Interferon by Stimulation of the Immune System, Interferons: From Molecular Biology to Clinical Application, Eds: D. C. Burke and A. G. Morris, Cambridge Univ. Press, 1983, pp. 149-179; P. I. Marcus, Chapter 10, Interferon Induction by Virus, Interferons and Their Applications, Eds: P. E. Came and W. A. Carter, Springer Verlag, (Handbook of Experimental Pharmacology V. 71) 1984, pp. 205-232; its proposed molecular characterizations; P. B. Sehgal, How Many Human Interferons Are There?. Interferon 1982, Ed: I. Gresser, Academic Press, 1982, pp. 1-22; J. Collins, Structure and Expression of the Human Interferon Genes, Interferons: From Molecular Biology to Clinical Application, Eds: D. C. Burke and A. G. Morris, Cambridge Univ. Press, 1983, pp. 35-65; K. C. Zoon and R. Wetzel, Chapter 5, Comparative Structures of Mammalian Interferons, 1a: Interferons and Their Applications, Eds: P. E. Came and W. A. Carter, Springer Verlag, (Handbook of Experimental Pharmacology V. 71) 1984, pp. 79-100; its clinical applications; M. Krim, Chapter 1, Interferons and Their Applications: Past, Present, and Future, Interferons and Their Applications, Eds: P. E. Came and W. A. Carter, Springer Verlag, (Handbook of Experimental Pharmacology V. 71) 1984; S. B. Greenberg and M. W. Harmon, Chapter 21, Clinical Use of Interferons: Localized Applications in Viral Diseases, Ibid. pp. 433-453; and proposed mechanisms of its antitumor, antiviral, and immune system activities. G. M. Scott, The Antiviral Effects of Interferon, From Molecular Biology to Clinical Application, Eds: D. C. Burke and A. G. Morris, Cambridge Univ. Press, 1983, pp. 279-311; M. McMahon and I. M. Kerr, The Biochemistry of the Antiviral State, Ibid. pp. 89-108; J. S. Malpas, The Antitumor Effects of Interferon, Ibid. pp. 313-327; J. Taylor-Papadimitrion, The Effects of Interferon on the Growth and Function of Normal and Malignant Cells, Ibid. pp. 109-147.
Because of the intensity and disparate origins of research concerning interferon and its characteristics and uses, there exists a substantial lack of uniformity in such matters as classification of interferon types. There are also numerous, sometimes contradictory, theories concerning the mode of action of interferon in producing clinical effects. The following brief summary of the current state of knowledge regarding interferon will aid in understanding the present invention.
Although originally isolated from cells of avian origin (chick allantoic cells), interferon production has been observed in cells of all classes of vertebrates, including mammals, amphibians, and reptiles. Interferon production by vertebrate cells is seldom spontaneous but is often readily "induced" by treatment of cells (in vivo or in vitro) with a variety of substances including viruses, nucleic acids (including those of viral origin as well as synthetic polynucleotides), lipopolysaccharides, and various antigens and mitogens.
Interferons have generally been named in terms of the species of animal cells producing the substance (e.g., human, murine, or bovine), the type of cell involved (e.g., leukocyte, lymphoblastoid, fibroblast) and, occasionally, the type of inducing material responsible for interferon production (e.g., virus, immune). Interferon has been loosely classified by some researchers according to induction mode as either Type I or Type II, with the former classification comprehending viral and nucleic acid induced interferon and the latter class including the material produced as a lymphokine through induction by antigens and mitogens. More recently, the international committee devising an orderly nomenclature system for interferon has classified interferon into types on the basis of antigenic specificities. In this newer classification, the designations alpha (.alpha.), beta (.beta.), and gamma (.gamma.) have been used to correspond to previous designations of leukocyte, fibroblast, and type II (immune) interferons, respectively. Alpha and beta interferons are usually acid-stable and correspond to what have been called type I interferons; gamma interferons are usually acid-labile and correspond to what has been called type II interferons. The international committee's nomenclature recommendations apply only to human and murine interferons. Journal of Interferon Research, 1 pp. vi (1980).
Determination of precise molecular structures for interferon was for some time beyond the capacities of the art. In the years since interferon was first characterized as proteinaceous on grounds of its inactivation by trypsin, attempts to purify and uniquely characterize were frustrated by its high specific activity as well as its apparent heterogeneity. Presently, some precision in determining molecular structure has been achieved for interferon. See P. B. Sehgal, supra,; J. Collins, supra; and K. C. Zoon and R. Wetzel, supra.
In its earliest applications, interferon was employed exclusively as an antiviral agent and the most successful clinical therapeutic applications to date have been in the treatment of viral or virus-related disease states. It became apparent, however, that exogenous interferon was sometimes capable of effecting regression or remission of various metastatic diseases. An overview of current clinical trials of interferon as an antiviral and antiproliferative therapeutic agent through early 1983 is contained in The Biology of the Interferon System 1983, Proceedings of the Second International TNO Meeting on the Biology of the Interferon System, Rotterdam, The Netherlands, Apr. 18-22, 1983, and Antiviral Research, Mar. 1983, Special Abstract Issue, Elsevier/North-Holland Biomedical Press, Netherlands.
The clinical agent of choice in this work has been human leukocyte interferon, "mass-produced" by procedures involving collection and purification of vast quantities of human buffy coat leukocytes, induction with virus, and isolation from culture media. The need for interferon of human source is, of course, consistent with the longstanding conclusion that interferon is "species specific," i.e., biologically active, in vivo, only in species homologous to the source cells.
In the work described above, interferon has been administered parenterally, i.e., intramuscularly and intradermally, with some successful topical and intranasal usages having been reported. It has seldom been administered intravenously because of substantial adverse effects attributable to "contaminants" in crude and even highly purified isolates. The invention of applicant described in U.S. Pat. No. 4,462,985, and in PCT International Application No. PCT/US 81/01103, filed Aug. 18, 1981, published Mar. 4, 1982 as WO 82/00588, the disclosures of which are hereby incorporated by reference, concerns the use of interferon of heterologous species origin, and also involves oral administration of interferon. Prior to these disclosures, there had been no reports of therapeutically successful oral administration of interferon. This circumstance was consistent with the widely held belief that interferon would not withstand exposure to a digestive environment such as that found in mammals.
In addition to use in antiviral and antitumor therapy, interferon has rather recently been noted to possess immunomodulatory effects, both immunopotentiating and immunosuppressive in nature. B. Lebleu and J. Content, Mechanisms of Interferon Action: Biochemical and Genetic Approaches, Interferon 1982, Ed: I. Gresser, Academic Press, 1982, pp. 47-94; M. Moore, Interferon and the Immune System, 2: Effect of IFN on the Immune System, Interferons: From Molecular Biology to Clinical Application, Eds: D. C. Burke and A. G. Morris, Cambridge Univ. Press, 1983, pp. 181-209; H. Smith-Johannsen, Y-T Hou, X-T Liu, and Y-H Tan, Chapter 6, Regulatory Control of Interferon Synthesis and Action, Interferons and Their Applications, Eds: P. E. Came and W. A. Carter, Springer Verlag, (Handbook of Experimental Pharmacology V. 71) 1984, pp. 101-135; J. L. Raylor, J. L. Sabram, and S. E. Grossberg, Chapter 9, The Cellular Effects of Interferon, Ibid. pp. 169-204; J. M. Zarling, Effects of Interferon and Its Inducers on Leukocytes and Their Immunologic Functions, Ibid. pp. 403-431; R. Ravel, The Interferon System in Man: Nature of the Interferon Molecules and Mode of Action, Antiviral Drugs and Interferon: The Molecular Basics of Their Activity, Ed: Y. Becker, Martinus Nijhoff Pub., 1984, pp. 357-433.
Further, "new" biological activities for exogenous and endogenous interferon are consistently being ascertained. K. Berg, M. Hokland, and I. Heron, Biological Activities of Pure HuIFN-Alpha Species, Interferon, Properties, Mode of Action, Production, Clinical Application, Eds: K. Munk and H., Kirchner, (Beitrage zur Onkologie V. 11) pp. 118-126; S. Pestka et al, The Specific Molecular Activities of Interferons Differe for Antiviral, Antiproliferative and Natural Killer Cell Activities, The Biology of the Interferon System, 1983, Eds: E. DeMaeyer and H. Schellekens, pp. 535-549; P. K. Weck and P. E. Came, Chapter 16, Comparative Biologic Activities of Human Interferons, Interferons and Their Applications, Eds: P. E. Came and W. A. Carter, Springer Verlag, (Handbook of Experimental Pharmacology V. 71) 1984, pp. 339-355.
Prior to the invention described and claimed in U.S. patent application Ser. No. 06/448,951, filed on Dec. 13, 1982, now U.S. Pat. No. 4,497,795, the disclosure of which is incorporated herein by reference, there had been no reports of the ability of interferon to regulate the appetite and efficiency of food utilization of warm-blooded vertebrates. That application discloses that interferon does have such activity.
One viral disease which has not been controlled, by interferon or other means, is bovine respiratory disease complex (BRDC). BRDC is an all-encompassing term describing an acute, contagious infection of cattle characterized by inflammation of the upper respiratory passages and trachea. BRDC leads to pneumonia with clinical signs of dyspnea, anorexia, fever, depression, mucopurulent nasal discharge and mucopurulent ocular discharge, all of which result in high morbidity and mortality. BRDC is a major cause of disease loss in beef cattle. The economic loss to cattlemen for treatment, weight loss, death loss, and culling is estimated to be $333,000,000 annually (National Cattlemen's Association, 1980).
When BRDC symptomology is observed in cattle after transport to feedlots or pastures, it is commonly called "shipping fever." On their way to the feedlot, calves are subjected to the stresses of intensive management techniques, transportation without food or water, and a variety of infectious agents. Upon arrival at the feedlot, processing exposes the calves to the additional stresses of weaning, castration, dehorning, branding, eartagging, worming, vaccination, and delousing. In many situations, calves are stressed still further by changes in diet and environmental factors.
The infectious agents to which calves entering the marketing system are exposed to include viruses (infectious bovine rhinotracheitis (IBR), parainfluenza type 3, bovine viral diarrhea, respiratory syncytical, adenoviruses, enteroviruses, rhinoviruses, parvoviruses, and reoviruses), bacteria (Pasteurella hemolytica, Pasteurella multocida, and Hemophilus somnus), mycoplasma (M. dispar, M. bovirhinis, M. bovis, and M. arginini), and Chlamydia.
The herpesvirus, IBR virus, is one of the infectious agents that is most commonly isolated by veterinary diagnostic laboratories in cases of BRDC. While some commercial vaccines for IBR are available, they have not been completely satisfactory in the past, partly because immunization of calves stressed by shipping can exacerbate the clinical signs of the disease. Also, some calves will not develop antibodies after vaccination, leaving them still susceptible to infection. Furthermore, many commercial vaccines are designed to provide protection no sooner than 14 days after vaccination, tracking the U.S. Department of Agriculture immunogenicity test. Because of the imperfections of the vaccination treatments used in the past and the enormous economic losses involved, a need exists for improved methods of preventing and treating bovine respiratory disease.
There is also a need for improved methods of regulating appetite and efficiency of feed utilization in warm-blooded vertebrates. In all the known previous interferon research, whether its goal was to assess antiviral, antiproliferative, or appetite regulating activity, the interferon dosages used have been generally high. Applicant has now made the surprising discovery that much lower dosages can produce superior effects.